Using the reported relative solubilities in the order of I > II > IV > III, the thermodynamic stability of the structures should increase in the order of I < II < IV < III (16). For sulfathiazole, crystallization from any solvent at a given temperature should initially give rise to the least stable form, followed by the stepwise conversion through the other metastable forms to the thermodynamically most stable Form III. But specific solvent–solute interactions might be needed to stabilize a particular form by inhibiting the nucleation and growth of the next most stable structure. Anwar reported that n-propanol could interfere with the completion of the β-sulfathiazole dimer in structures of Forms II, III, and IV because of its donor–acceptor duality (17). This could be why the efficiency of blocking the formation of a β ring in structures of Forms II, III, and IV increased in the order of water < methanol < ethanol < n-propanol < benzyl alcohol, as reflected by the decreasing amount of Forms III and IV in the DSC profiles (see Figures 8d, 8f, 8h, 8j, and 8k). On the other hand, solvents such as THF and DMF that lack a donor hydrogen and have lower Hansen hydrogen-bonding parameter (δ_h) values were unable to stabilize the transition state and gave a pure Form III structure without any trace of Form I seeds (see Figures 8b and 8g).

The kinetics effects of solvents on the crystallization of sulfathiazole polymorphs were also noticed in binary and ternary systems (16). Although sulfathiazole forms solvates, TGA scans verified that all sulfathiazole crystals produced were neither solvates nor hydrates because no weight loss upon heating was observed before the melting point of 203 °C (19). DSC responses of the sulfathiazole crystals grown in the 13 solvent mixtures of (acetonitrile:n-propanol:water) in Figure 9 showed that the crystals contained (polymorphs): (100:0:0) (Forms I, III, and IV), (0:100:0) (Forms I and V), (0:0:100) (Forms I and III), (50:50:0) (Forms I, III, and IV), (80:10:10) (Forms II, III, IV, and V), (45:45:10) (Forms I and V), (10:80:10) (Forms I, III, and IV), (60:20:20) (Forms I and V), (20:60:20) (Forms I, III, and IV), (33:33:33) (Forms II and III), (10:45:45) (Forms I and VI), (0:50:50) (Forms I, III, and IV), (45:10:45) (Forms I, III, and IV), (20:20:60) (Forms I, III, and IV), (50:0:50) (Forms I, III, IV, and V) and (10:10:80) (Forms I, III, and IV).

The endotherm at 203 °C was the melting point of Form I, which also might have been produced by the enantiotropic transformation of Forms III, IV, V, and VI upon heating in the DSC (29). But this time, Form II was observed for solids generated by the ternary solvent mixtures of (80:10:10) and (33:33:33) (see Figures 9e and 9j). Moreover, an endotherm that appeared at a relatively low 135 °C for the ternary solvent mixture of (10:45:45) (see Figure 9k) was considered a newly discovered polymorph for sulfathiazole, conventionally Form VI (29).